High sodium intake, independent of blood pressure, is associated with increased cardiovascular risk. However, the genetic cause(s) of salt sensitivity is not known. The definitive evidence to link genes to complex diseases, such as hypertension and salt sensitivity is the swapping of one phenotype for another. G protein-coupled receptor kinase 4 (GRK4) is the only gene postulated as causal of hypertension that fulfills this criterion, i.e., GRK4 gene variants produce salt sensitivity and hypertension in mice. GRK43 142V transgenic mice develop salt-resistant hypertension while GRK43 486V transgenic mice develop salt-sensitive hypertension. Depending upon the genetic background, overexpression of GRK43 wild type converts a salt- sensitive mouse (C57BL/6J) to a salt-resistant mouse while overexpression of GRK43 486V converts a salt- resistant mouse (SJL/J) to salt-sensitive mouse. The overall objective is to test the hypothesis that human GRK43 wild type imparts salt resistance while human GRK43 486V causes salt-sensitive hypertension. Aim 1 will test the hypothesis that human GRK43 wild type causes salt resistance by facilitating sodium excretion. This change in phenotype is due, in part, to human GRK43 wild type differential regulation of GPCRs (e.g., D1R and AT1R) involved in the control of renal NaCl transport and blood pressure. Aim 2 will test the hypothesis that human GRK43 486V causes salt-sensitive hypertension, in part, by impairing renal D1R function and enhancing AT1R expression. The effect of knockout of GRK4 and targeted gene replacement with human GRK43 wild type gene and variants (486V) in mice on the regulation of renal sodium excretion and blood pressure will be studied. These studies will enable the deciphering of the mechanism of salt sensitivity and its impact on blood pressure. A modest reduction in salt intake in children, adolescents, and adults results in an immediate decrease in blood pressure, with long term benefits. However, dietary sodium restriction may not be beneficial to all. Lifestyle changes lower blood pressure and reduces cardiovascular risk but motivation is a problem. Results from these studies may be important in formulating diagnostic tests, drug therapy (pharmacogenomics) and lifestyle modification. PUBLIC HEALTH RELEVANCE: Variants of a gene called GRK4 predict with 70-90% accuracy that blood pressure will rise with increased salt intake. Diuretics are more effective in lowering blood pressure in individuals with variants of this gene. Results from these studies will be beneficial in the formulation of diagnostic tests, as well as drug therapy (pharmacogenomics) and lifestyle modification.